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Mechanism Of Action
Enfuvirtide is an antiviral drug [see Microbiology].
The pharmacokinetic properties of enfuvirtide were evaluated in HIV-1 infected adult and pediatric subjects.
Following a 90-mg single subcutaneous injection of FUZEON into the abdomen in 12 HIV-1 infected subjects, the mean (±SD) Cmax was 4.59 ± 1.5 μg/mL, AUC was 55.8 ± 12.1 μg•h/mL and the median Tmax was 8 hours (ranged from 3 to 12 h). The absolute bioavailability (using a 90-mg intravenous dose as a reference) was 84.3% ± 15.5%. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean (±SD) steady-state Cmax was 5.0 ± 1.7 μg/mL, Ctrough was 3.3 ± 1.6 μg/mL, AUC0-12h was 48.7 ± 19.1 μg•h/mL, and the median Tmax was 4 hours (ranged from 4 to 8 h).
Absorption of the 90-mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh or arm.
The mean (±SD) steady-state volume of distribution after intravenous administration of a 90-mg dose of FUZEON (N=12) was 5.5 ± 1.1 L.
Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 μg/mL. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein.
The CSF levels of enfuvirtide (measured from 2 hours to 18 hours after administration of enfuvirtide) in 4 HIVinfected subjects were below the limit of quantification (0.025 μg/mL).
Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.
In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3. The hydrolysis reaction is not NADPH dependent. The M3 metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.
Following a 90-mg single subcutaneous dose of enfuvirtide (N=12) the mean ±SD elimination half-life of enfuvirtide is 3.8 ± 0.6 h and the mean ±SD apparent clearance was 24.8 ± 4.1 mL/h/kg. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean ±SD apparent clearance was 30.6 ± 10.6 mL/h/kg.
Formal pharmacokinetic studies of enfuvirtide have not been conducted in subjects with hepatic impairment.
Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. The results of a renal impairment study indicate clearance of enfuvirtide was reduced by 38% in subjects with severe renal impairment (CL = 11 –35 mL/min; n = 4) and by 14 - 28% in subjects with end-stage renal disease maintained on dialysis (n = 8) compared to subjects with normal renal function (CL > 80 mL/min; n = 8). Hemodialysis did not significantly alter enfuvirtide clearance.
No dose adjustment is recommended for patients with impaired renal function.
Gender and Weight
Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males after adjusting for body weight.
Enfuvirtide clearance decreases with decreased body weight irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.
No dose adjustment is recommended for weight or gender.
Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide was not different in Blacks compared to Caucasians. Other pharmacokinetic studies suggest no difference between Asians and Caucasians after adjusting for body weight.
The pharmacokinetics of enfuvirtide have been studied in 23 pediatric subjects aged 6 through 16 years at a dose of 2 mg/kg. Enfuvirtide pharmacokinetics were determined in the presence of concomitant medications including antiretroviral agents. A dose of 2 mg/kg twice daily (maximum 90 mg twice daily) provided enfuvirtide plasma concentrations similar to those obtained in adult subjects receiving 90 mg twice daily.
In the 23 pediatric subjects receiving the 2 mg/kg twice daily dose, the mean ±SD steady-state AUC was 56.3 ± 22.3 μg•h/mL, Cmax was 6.3 ± 2.4 μg/mL, Ctrough was 3.1 ± 1.5 μg/mL, and apparent clearance was 40 ± 17 mL/h/kg [see Use in Specific Populations].
The pharmacokinetics of enfuvirtide have not been studied in patients over 65 years of age.
See also DRUG INTERACTIONS
Table 5 :Effect of Ritonavir, Saquinavir/Ritonavir, and
Rifampin on the Steady-State Pharmacokinetics of Enfuvirtide (90 mg bid)*
|Coadministered Drug||Dose of Coadministered Drug||N||% Change of Enfuvirtide Pharmacokinetic Parameters†x (90% CI)|
|Ritonavir||200 mg, q12h, 4 days||12||↑24
(↑9 to ↑41)
(↑8 to ↑37)
(↑2 to ↑28)
|Saquinavir/ Ritonavir||1000/100 mg, q12h, 4 days||12||↔||↑14
(↑5 to ↑24)
|Rifampin||600 mg, qd, 10 days||12||↔||↔||↓15
(↓22 to ↓7)
|* All studies were performed in HIV-1+ subjects using a
sequential crossover design.
† ↑= Increase; ↓ = Decrease;↔ = No Effect (↑ or ↓ < 10%)
x No interactions were clinically significant.
Mechanism of Action
Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.
Antiviral Activity in Cell Culture
The antiviral activity of enfuvirtide was assessed by infecting different CD4 cell types with laboratory and clinical isolates of HIV-1. The median EC50 value for baseline clinical isolates was 4.10 nM (ranged from 0.089 to 107 nM; 0.4 to 480 ng/mL) by the cMAGI assay (n=130) and was 55.9 nM (1.56 to 1675 nM; 7 to 7526 ng/mL) by a recombinant phenotypic entry assay (n=627). Enfuvirtide was similarly active in cell culture against clades A, AE, C, D, F, and G (median EC50 value was 7.01 nM; range 3.78 to 27.9 nM; 17-126 ng/mL), and R5, X4, and dual tropic viruses. Enfuvirtide has no activity against HIV-2.
Enfuvirtide exhibited additive to synergistic effects in cell culture assays when combined with individual members of various antiretroviral classes, including lamivudine, zidovudine, indinavir, nelfinavir, and efavirenz.
HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in cell culture. Genotypic analysis of these resistant isolates showed mutations that resulted in amino acid substitutions at the enfuvirtide binding HR1 domain positions 36 to 38 of the HIV-1 envelope glycoprotein gp41. Phenotypic analysis of site-directed mutants in positions 36 to 38 in an HIV-1 molecular clone showed a 5-fold to 684-fold decrease in susceptibility to enfuvirtide.
In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from subjects failing a FUZEON containing regimen. Posttreatment HIV-1 virus from 277 subjects experiencing protocol defined virological failure at 48 weeks exhibited a median decrease in susceptibility to enfuvirtide of 33.4-fold (range 0.4-6318-fold) relative to their respective baseline virus. Of these, 249 had decreases in susceptibility to enfuvirtide of greater than 4-fold and all but 3 of those 249 exhibited genotypic changes in the codons encoding gp41 HR1 domain amino acids 36 to 45. Substitutions in this region were observed with decreasing frequency at amino acid positions 38, 43, 36, 40, 42, and 45. Mutations or polymorphisms in other regions of the envelope (e.g., the HR2 region or those yet to be identified) as well as co-receptor usage and density may affect susceptibility to enfuvirtide.
HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) were susceptible to enfuvirtide in cell culture.
Description Of Clinical Studies
Studies in Antiretroviral Experienced Patients
T20-301 and T20-302 were randomized, controlled, open-label, multicenter trials in HIV-1 infected subjects. Subjects were required to have either (1) viremia despite 3 to 6 months prior therapy with a nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), and protease inhibitor (PI) or (2) viremia and documented resistance or intolerance to at least one member in each of the NRTI, NNRTI, and PI classes.
All subjects received an individualized background regimen consisting of 3 to 5 antiretroviral agents selected on the basis of the subject's prior treatment history and baseline genotypic and phenotypic viral resistance measurements. Subjects were then randomized at a 2:1 ratio to FUZEON 90 mg twice daily with background regimen or background regimen alone.
After week 8, subjects on either treatment arm who met protocol defined criteria for virological failure were permitted to revise their background regimens; those on background regimen alone were also permitted to add FUZEON.
Demographic characteristics for studies T20-301 and T20-302 are shown in Table 6. Subjects had prior exposure to a median of 12 antiretrovirals for a median of 7 years.
Table 6 :T20-301 and T20-302 Pooled Subject Demographics
|FUZEON + Background Regimen
|Mean Age (yr) (range)||42 (16-67)||43 (24-82)|
|Median Baseline HIV-1 RNA (log10 copies/mL) (range)||5.2 (3.5-6.7)||5.1 (3.7-7.1)|
|Median Baseline CD4 Cell Count (cells/mm ) (range)||89 (1-994)||97 (1-847)|
The disposition and efficacy outcomes of T20-301 and T20-302 are shown in Table 7.
Table 7 :Outcomes at Week 48 (Pooled Studies T20-301 and
|Outcomes||FUZEON + Background Regimen 90 mg bid
|Virological Responder (at least 1 log10 below baseline)||304 (46%)||61 (18%)|
||0 191||220 (66%)|
|Continued Background Regimen
|Switched to FUZEON
|Discontinued due to insufficient treatment response#||37 (5%)||13 (12%)||22 (10%)|
|Discontinued due to adverse reactions/intercurrent illness/labs||46 (7%)||9 (8%)||13 (6%)|
|Deaths||15 (2%)||5 (4%)||2 (1%)|
|Discontinued due to injection:
||27 (4%)||NA||10 (5%)|
||18 (3%)||NA||2 (1%)|
|Discontinued due to other reasons†||25 (4%)||14 (13%)||6 (3%)|
|*Includes never responded, rebound, and missing RNA data.
#Includes study discontinuation for virological failure and insufficient response as per the judgment of the investigator.
##Includes difficulties with injection, such as injection fatigue and inconvenience.
†Includes lost to follow-up, treatment refusal, and non-compliance.
At 48 weeks, 154 (23%) of subjects in the FUZEON+background regimen and 27 (8%) in the background regimen alone had HIV-1 RNA levels < 50 copies/mL, and 225 (34%) of subjects receiving FUZEON+background regimen had HIV-1 RNA levels < 400 copies/mL compared to 44 (13%) in the background regimen alone. Subjects achieving HIV-1 RNA levels < 50 copies/mL were included in the < 400 copies/mL category and both categories were incorporated in the overall virologic responder category of achieving HIV-1 RNA at least 1 log10 below baseline.
The mean log change in HIV-1 RNA from baseline was -1.4 log10 copies/mL in subjects receiving FUZEON+background and -0.5 in those receiving background alone. The mean change in CD4 cell count from baseline to week 48 was +91 cells/mm³ in the FUZEON+background arm and +45 cells/mm³ in the background alone arm.
Subjects in the FUZEON+background arm achieved a better virologic and immunologic outcome than subjects in the background alone arm across all subgroups based on baseline CD4 cell count, baseline HIV-1 RNA, number of prior ARVs or number of active ARVs in the background regimen.
Last reviewed on RxList: 12/14/2015
This monograph has been modified to include the generic and brand name in many instances.
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